Erythropoietin as a New Therapeutic Tool for Apnea of Prematurity: Data From an Animal Model

Introduction: Owing to immaturity of the brain, apnea of prematurity (AoP) occurs in more than 85% of infants born with less than 34 weeks of gestational age. AoP is associated with severe and repeated episodes of arterial oxygen desaturation (intermittent hypoxia [IH]), which in turn slows up the maturation and development of the brain, induces oxidative stress, and decreases antioxidative defenses. Interestingly, clinical and basic (in rodents) studies showed that the erythropoietin (Epo) produced by neurons and astrocytes is a power antioxidant factor that protects the newborn brain against hypoxic-ischemic injury. Moreover, our research showed that Epo is a potent respiratory stimulant by interacting with the respiratory centers of the brain stem. Accordingly, we hypothesized in an animal model that Epo can protect newborns rats against the consequences of IH induced by AoP. As caffeine (despite being ineffective in ~50% of cases) is the treatment of choice of AoP, the effects of Epo and caffeine were compared.

Materials and Methods: Newborn rats exposed to IH during postnatal days (P) 3 to 10 were used in this work. During this time, animals were daily gavaged with vehicle, Epo, caffeine, and Epo + caffeine (10–12 pups/group). At P10, the frequency of apneas at rest was measured (as index of respiratory dysfunction induced by IH) with plethysmography. Subsequently, tissues from hippocampus, cortex, and brain stem were collected, and the activity of Superoxide dismutase (SOD—major antioxidant) and NADPH oxidase (NOX—major prooxidant) enzymes were evaluated.

Results: IH increased the frequency of apnea, reduced SOD, but increased NOX activity. Interestingly, Epo and caffeine significantly reduced apnea frequency, but only Epo efficiently restored the oxidant activity to normal levels. Moreover, the administration of Epo and caffeine together provided cumulative beneficial effects in reducing the apneic episodes.

Conclusion: Our animal model provides evidence suggesting that Epo and caffeine activate different, but complementary mechanisms to decrease apneas, suggesting that combined Epo + caffeine treatment could be clinically relevant against AoP.

Keywords: apnea, newborn, intermittent hypoxia, oxidative stress, cytokines, neuroprotection